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Endocrinology

Subclinical hypothyroidism, outcomes and management guidelines: a narrative review and update of recent literature

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Pages 351-365 | Received 16 Nov 2022, Accepted 15 Dec 2022, Published online: 18 Jan 2023

References

  • Sheehan MT. Biochemical testing of the thyroid: TSH is the best and, oftentimes, only test needed - a review for primary care. Clin Med Res. 2016;14(2):83–92.
  • Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol. 2016;84(6):799–808.
  • National Institute for Health and Care Excellence. Hypothyroidism: What are the complications? May 2021; [cited 2022 Aug]. Available from: https://cks.nice.org.uk/topics/hypothyroidism/background-information/complications/.
  • Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–228.
  • Lazarus J, Brown RS, Daumerie C, et al. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76–94.
  • Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389.
  • Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365:l2006.
  • Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American association of clinical endocrinologists and the American thyroid association. Thyroid. 2012;22(12):1200–1235.
  • Luongo C, Dentice M, Salvatore D. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol. 2019;15(8):479–488.
  • Sabatino L, Vassalle C, Del Seppia C, et al. Deiodinases and the three types of thyroid hormone deiodination reactions. Endocrinol Metab. 2021;36(5):952–964.
  • Al Eidan E, Ur Rahman S, Al Qahtani S, et al. Prevalence of subclinical hypothyroidism in adults visiting primary health-care setting in Riyadh. J Community Hosp Intern Med Perspect. 2018;8(1):11–15.
  • Hennessey JV, Espaillat R. Subclinical hypothyroidism: a historical view and shifting prevalence. Int J Clin Pract. 2015;69(7):771–782.
  • Yoo WS, Chung HK. Subclinical hypothyroidism: prevalence, health impact, and treatment landscape. Endocrinol Metab. 2021;36(3):500–513.
  • Chaker L, Razvi S, Bensenor IM, et al. Hypothyroidism. Nat Rev Dis Primers. 2022;8(1):30.
  • Asvold BO, Vatten LJ, Bjøro T. Changes in the prevalence of hypothyroidism: the HUNT study in Norway. Eur J Endocrinol. 2013;169(5):613–620.
  • Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489–499.
  • Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol. 2014;171(5):R197–R208.
  • Razvi S, Bhana S, Mrabeti S. Challenges in interpreting thyroid stimulating hormone results in the diagnosis of thyroid dysfunction. J Thyroid Res. 2019;2019:4106816.
  • Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76–131.
  • Javaid U, Kennedy D, Addison C, et al. Frequency, determinants and costs of thyroid function testing in a laboratory serving a large population. Eur J Endocrinol. 2022;186(5):553–560.
  • Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87(7):3221–3226.
  • Meyerovitch J, Rotman-Pikielny P, Sherf M, et al. Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. Arch Intern Med. 2007;167(14):1533–1538.
  • Somwaru LL, Rariy CM, Arnold AM, et al. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. J Clin Endocrinol Metab. 2012;97(6):1962–1969.
  • Imaizumi M, Sera N, Ueki I, et al. Risk for progression to overt hypothyroidism in an elderly Japanese population with subclinical hypothyroidism. Thyroid. 2011;21(11):1177–1182.
  • Díez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004;89(10):4890–4897.
  • Walsh JP, Bremner AP, Feddema P, et al. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. J Clin Endocrinol Metab. 2010;95(3):1095–1104.
  • Javed Z, Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016;7(1):12–23.
  • Liu P, Liu R, Chen X, et al. Can levothyroxine treatment reduce urinary albumin excretion rate in patients with early type 2 diabetic nephropathy and subclinical hypothyroidism? A randomized double-blind and placebo-controlled study. Curr Med Res Opin. 2015;31(12):2233–2240.
  • Li X, Wang Y, Guan Q, et al. The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: a systematic review and meta-analysis of randomized controlled trials. Clin Endocrinol. 2017;87(1):1–9.
  • Liu XL, He S, Zhang SF, et al. Alteration of lipid profile in subclinical hypothyroidism: a meta-analysis. Med Sci Monit. 2014;20:1432–1441.
  • Abreu IM, Lau E, de Sousa Pinto B, et al. Subclinical hypothyroidism: to treat or not to treat, that is the question! a systematic review with meta-analysis on lipid profile. Endocr Connect. 2017;6(3):188–199.
  • Zhao M, Liu L, Wang F, et al. A worthy finding: decrease in total cholesterol and low-density lipoprotein cholesterol in treated mild subclinical hypothyroidism. Thyroid. 2016;26(8):1019–1029.
  • Brenta G, Berg G, Miksztowicz V, et al. Atherogenic lipoproteins in subclinical hypothyroidism and their relationship with hepatic lipase activity: response to replacement treatment with levothyroxine. Thyroid. 2016;26(3):365–372.
  • Pergialiotis V, Konstantopoulos P, Prodromidou A, et al. Management of Endocrine Disease: the impact of subclinical hypothyroidism on anthropometric characteristics, lipid, glucose and hormonal profile of PCOS patients: a systematic review and meta-analysis. Eur J Endocrinol. 2017;176(3):R159–R166.
  • Xing Y, Chen J, Liu J, et al. The impact of subclinical hypothyroidism on patients with polycystic ovary syndrome: a meta-analysis. Horm Metab Res. 2021;53(6):382–390.
  • de Medeiros SF, de Medeiros MAS, Ormond CM, et al. Subclinical hypothyroidism impact on the characteristics of patients with polycystic ovary syndrome: a meta-analysis of observational studies. Gynecol Obstet Invest. 2018;83(2):105–115.
  • Cassar S, Misso ML, Hopkins WG, et al. Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Hum Reprod. 2016;31(11):2619–2631.
  • Ding X, Yang L, Wang J, et al. Subclinical hypothyroidism in polycystic ovary syndrome: a systematic review and meta-analysis. Front Endocrinol. 2018;9:700.
  • Ding X, Zhao Y, Zhu CY, et al. The association between subclinical hypothyroidism and metabolic syndrome: an update meta-analysis of observational studies. Endocr J. 2021;68(9):1043–1056.
  • Yang L, Lv X, Yue F, et al. Subclinical hypothyroidism and the risk of metabolic syndrome: a meta-analysis of observational studies. Endocr Res. 2016;41(2):158–165.
  • Eftekharzadeh A, Khamseh ME, Farshchi A, et al. The association between subclinical hypothyroidism and metabolic syndrome as defined by the ATP III criteria. Metab Syndr Relat Disord. 2016;14(3):137–144.
  • Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA. 2018;320(13):1349–1359.
  • Neves JS, Castro Oliveira S, Souteiro P, et al. Effect of weight loss after bariatric surgery on thyroid-stimulating hormone levels in patients with morbid obesity and normal thyroid function. Obes Surg. 2018;28(1):97–103.
  • Azran C, Hanhan-Shamshoum N, Irshied T, et al. Hypothyroidism and levothyroxine therapy following bariatric surgery: a systematic review, meta-analysis, network meta-analysis, and meta-regression. Surg Obes Relat Dis. 2021;17(6):1206–1217.
  • Guan B, Chen Y, Yang J, et al. Effect of bariatric surgery on thyroid function in obese patients: a systematic review and meta-analysis. Obes Surg. 2017;27(12):3292–3305.
  • Cordido M, Juiz-Valiña P, Urones P, et al. Thyroid function alteration in obesity and the effect of bariatric surgery. J Clin Med. 2022;11(5):1340.
  • Farghaly HS, Metwalley KA, Raafat DM, et al. Epicardial fat thickness in children with subclinical hypothyroidism and its relationship to subclinical atherosclerosis: a pilot study. Horm Res Paediatr. 2019;92(2):99–105.
  • Yao K, Zhao T, Zeng L, et al. Non-invasive markers of cardiovascular risk in patients with subclinical hypothyroidism: a systematic review and meta-analysis of 27 case control studies. Sci Rep. 2018;8(1):4579.
  • Willeit P, Tschiderer L, Allara E, et al. Carotid intima-media thickness progression as surrogate marker for cardiovascular risk: meta-analysis of 119 clinical trials involving 100,667 patients. Circulation. 2020;142(7):621–642.
  • Blum MR, Gencer B, Adam L, et al. Impact of thyroid hormone therapy on atherosclerosis in the elderly with subclinical hypothyroidism: a randomized trial. J Clin Endocrinol Metab. 2018;103(8):2988–2997.
  • Soto-García AJ, Elizondo-Riojas G, Rodriguez-Gutiérrez R, et al. Carotid intima-media thickness in patients with subclinical hypothyroidism: a prospective controlled study. Clin Invest Med. 2021;44(4):E39–E45.
  • Gong N, Gao C, Chen X, et al. Endothelial function in patients with subclinical hypothyroidism: a meta-analysis. Horm Metab Res. 2019;51(11):691–702.
  • Gao N, Zhang W, Zhang YZ, et al. Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis. 2013;227(1):18–25.
  • Zhao T, Chen B, Zhou Y, et al. Effect of levothyroxine on the progression of carotid intima-media thickness in subclinical hypothyroidism patients: a meta-analysis. BMJ Open. 2017;7(10):e016053.
  • Aziz M, Kandimalla Y, Machavarapu A, et al. Effect of thyroxin treatment on carotid intima-media thickness (CIMT) reduction in patients with subclinical hypothyroidism (SCH): a meta-analysis of clinical trials. J Atheroscler Thromb. 2017;24(7):643–659.
  • Hennessey JV, Espaillat R. Diagnosis and management of subclinical hypothyroidism in elderly adults: a review of the literature. J Am Geriatr Soc. 2015;63(8):1663–1673.
  • Nakova VV, Krstevska B, Kostovska ES, et al. The effect of levothyroxine treatment on left ventricular function in subclinical hypothyroidism. Arch Endocrinol Metab. 2018;62(4):392–398.
  • Ilic S, Tadic M, Ivanovic B, et al. Left and right ventricular structure and function in subclinical hypothyroidism: the effects of one-year levothyroxine treatment. Med Sci Monit. 2013;19:960–968.
  • Madathil A, Hollingsworth KG, Blamire AM, et al. Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study. J Clin Endocrinol Metab. 2015;100(4):E607–E610.
  • Yao Z, Gao X, Liu M, et al. Diffuse myocardial injuries are present in subclinical hypothyroidism: a clinical study using myocardial t1-mapping quantification. Sci Rep. 2018;8(1):4999.
  • Chen X, Zhang N, Cai Y, et al. Evaluation of left ventricular diastolic function using tissue Doppler echocardiography and conventional doppler echocardiography in patients with subclinical hypothyroidism aged <60 years: a meta-analysis. J Cardiol. 2013;61:8–15.
  • Wang X, Wang H, Li Q, et al. Effect of levothyroxine supplementation on the cardiac morphology and function in patients with subclinical hypothyroidism: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2022;2022:dgac417.
  • Sato Y, Yoshihisa A, Kimishima Y, et al. Subclinical hypothyroidism is associated with adverse prognosis in heart failure patients. Can J Cardiol. 2018;34(1):80–87.
  • Kannan L, Shaw PA, Morley MP, et al. Thyroid dysfunction in heart failure and cardiovascular outcomes. Circ Heart Fail. 2018;11(12):e005266.
  • Yang G, Wang Y, Ma A, et al. Subclinical thyroid dysfunction is associated with adverse prognosis in heart failure patients with reduced ejection fraction. BMC Cardiovasc Disord. 2019;19(1):83.
  • Jabbar A, Ingoe L, Junejo S, et al. Effect of levothyroxine on left ventricular ejection fraction in patients with subclinical hypothyroidism and acute myocardial infarction: a randomized clinical trial. JAMA. 2020;324(3):249–258.
  • Gencer B, Moutzouri E, Blum MR, et al. The impact of levothyroxine on cardiac function in older adults with mild subclinical hypothyroidism: a randomized clinical trial. Am J Med. 2020;133(7):848–856.e5.
  • Cai P, Peng Y, Chen Y, et al. Blood pressure characteristics of subclinical hypothyroidism: an observation study combined with office blood pressure and 24-h ambulatory blood pressure. J Hypertens. 2021;39(3):453–460.
  • Kim J, Prasitlumkum N, Randhawa S, et al. Association between subclinical hypothyroidism and incident hypertension in women: a systematic review and meta-analysis. J Clin Med. 2021;10(15):3318.
  • Ye Y, Xie H, Zeng Y, et al. Association between subclinical hypothyroidism and blood pressure–a meta-analysis of observational studies. Endocr Pract. 2014;20(2):150–158.
  • He W, Li S, Zhang JA, et al. Effect of levothyroxine on blood pressure in patients with subclinical hypothyroidism: a systematic review and meta-analysis. Front Endocrinol. 2018;9:454.
  • Lai Y, Wang H, Xia X, et al. Serum fibroblast growth factor 19 is decreased in patients with overt hypothyroidism and subclinical hypothyroidism. Medicine. 2016;95(39):e5001.
  • Lupoli R, Di Minno MN, Tortora A, et al. Primary and secondary hemostasis in patients with subclinical hypothyroidism: effect of levothyroxine treatment. J Clin Endocrinol Metab. 2015;100(7):2659–2665.
  • Xu Q, Wang Y, Shen X, et al. The effect of subclinical hypothyroidism on coagulation and fibrinolysis: a systematic review and meta-analysis. Front Endocrinol. 2022;13:861746.
  • Zhang SF, Li LZ, Zhang W, et al. Association between plasma homocysteine levels and subclinical hypothyroidism in adult subjects: a meta-analysis. Horm Metab Res. 2020;52(9):625–638.
  • Moon S, Kong SH, Choi HS, et al. Relation of subclinical hypothyroidism is associated with cardiovascular events and all-cause mortality in adults with high cardiovascular risk. Am J Cardiol. 2018;122(4):571–577.
  • Kim TH, Choi HS, Bae JC, et al. Subclinical hypothyroidism in addition to common risk scores for prediction of cardiovascular disease: a 10-year community-based cohort study. Eur J Endocrinol. 2014;171(5):649–657.
  • Lee Y, Lim YH, Shin JH, et al. Impact of subclinical hypothyroidism on clinical outcomes following percutaneous coronary intervention. Int J Cardiol. 2018;253:155–160.
  • Fang H, Zhao R, Cui S, et al. Sex differences in major cardiovascular outcomes and fractures in patients with subclinical thyroid dysfunction: a systematic review and meta-analysis. Aging. 2022;14:204352.
  • Moon S, Kim MJ, Yu JM, et al. Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Thyroid. 2018;28(9):1101–1110.
  • Peng CC, Huang HK, Wu BB, et al. Association of thyroid hormone therapy with mortality in subclinical hypothyroidism: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2021;106(1):292–303.
  • Collet TH, Bauer DC, Cappola AR, et al. Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J Clin Endocrinol Metab. 2014;99(9):3353–3362.
  • Zhang X, Xie Y, Ding C, et al. Subclinical hypothyroidism and risk of cerebral small vessel disease: a hospital-based observational study. Clin Endocrinol. 2017;87(5):581–586.
  • Chaker L, Baumgartner C, Ikram MA, et al. Subclinical thyroid dysfunction and the risk of stroke: a systematic review and meta-analysis. Eur J Epidemiol. 2014;29(11):791–800.
  • Alwan H, Villoz F, Feller M, et al. Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies. Eur J Endocrinol. 2022;187(5):S35–S46.
  • Han C, He X, Xia X, et al. Subclinical hypothyroidism and type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2015;10(8):e0135233.
  • Wu J, Yue S, Geng J, et al. Relationship between diabetic retinopathy and subclinical hypothyroidism: a meta-analysis. Sci Rep. 2015;5:12212.
  • Fighera TM, Perez CL, Faris N, et al. TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease. Endokrynol Pol. 2015;66(6):480–485.
  • Amado A, Castro B, Torre AP, et al. Serum TSH as a predictor of malignancy in indeterminate thyroid nodules. Ann R Coll Surg Engl. 2022;104(5):380–384.
  • Kim TH, Lee MY, Jin SM, et al. The association between serum concentration of thyroid hormones and thyroid cancer: a cohort study. Endocr Relat Cancer. 2022;29(12):635–644.
  • Tseng FY, Lin WY, Li CI, et al. Subclinical hypothyroidism is associated with increased risk for cancer mortality in adult Taiwanese-a 10 years population-based cohort. PLoS One. 2015;10(4):e0122955.
  • Boursi B, Haynes K, Mamtani R, et al. Thyroid dysfunction, thyroid hormone replacement and colorectal cancer risk. J Natl Cancer Inst. 2015;107:djv084.
  • Waring AC, Harrison S, Samuels MH, et al. Thyroid function and mortality in older men: a prospective study. J Clin Endocrinol Metab. 2012;97(3):862–870.
  • Pinter M, Haupt L, Hucke F, et al. The impact of thyroid hormones on patients with hepatocellular carcinoma. PLoS One. 2017;12(8):e0181878.
  • Leng T, Li X, Zhang H. Levothyroxine treatment for subclinical hypothyroidism improves the rate of live births in pregnant women with recurrent pregnancy loss: a randomized clinical trial. Gynecol Endocrinol. 2022;38(6):488–494.
  • Varner MW, Mele L, Casey BM, et al. Thyroid function in neonates of women with subclinical hypothyroidism or hypothyroxinemia. J Perinatol. 2018;38(11):1490–1495.
  • Casey BM, Thom EA, Peaceman AM, et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med. 2017;376(9):815–825.
  • Ma L, Qi H, Chai X, et al. The effects of screening and intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter single-blind, randomized, controlled study of thyroid function screening test during pregnancy. J Matern Fetal Neonatal Med. 2016;29(9):1391–1394.
  • Yoshihara H, Sugiura-Ogasawara M, Goto S, et al. Levothyroxine and subclinical hypothyroidism in patients with recurrent pregnancy loss. Am J Reprod Immunol. 2021;85(3):e13341.
  • Zhang B, Wang J, Shen S, et al. Subclinical hypothyroidism is not a risk factor for polycystic ovary syndrome in obese women of reproductive age. Gynecol Endocrinol. 2018;34(10):875–879.
  • Cai Y, Zhong L, Guan J, et al. Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol. 2017;15(1):39.
  • Maraka S, Mwangi R, McCoy RG, et al. Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ. 2017;356:i6865.
  • Plowden TC, Schisterman EF, Sjaarda LA, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(6):2358–2365.
  • Bernardi LA, Cohen RN, Stephenson MD. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Fertil Steril. 2013;100(5):1326–1331.
  • Han Y, Wang J, Wang X, et al. Relationship between subclinical hypothyroidism in pregnancy and hypertensive disorder of pregnancy: a systematic review and meta-analysis. Front Endocrinol. 2022;13:823710.
  • Ding Z, Liu Y, Maraka S, et al. Pregnancy and neonatal outcomes with levothyroxine treatment in women with subclinical hypothyroidism based on new diagnostic criteria: a systematic review and meta-analysis. Front Endocrinol. 2021;12:797423.
  • Bein M, Yu OHY, Grandi SM, et al. Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis. BMC Endocr Disord. 2021;21(1):34.
  • Dong AC, Morgan J, Kane M, et al. Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2020;113(3):587–600.e1.
  • Nazarpour S, Ramezani Tehrani F, Amiri M, et al. Levothyroxine treatment and pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis. Arch Gynecol Obstet. 2019;300(4):805–819.
  • Akhtar MA, Agrawal R, Brown J, et al. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev. 2019;6(6):CD011009.
  • Jia M, Wu Y, Lin B, et al. Meta-analysis of the association between maternal subclinical hypothyroidism and gestational diabetes mellitus. Int J Gynaecol Obstet. 2019;144(3):239–247.
  • Rao M, Zeng Z, Zhao S, et al. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2018;16(1):92.
  • Yamamoto JM, Benham JL, Nerenberg KA, et al. Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2018;8(9):e022837.
  • Liu Y, Chen H, Jing C, et al. The association between maternal subclinical hypothyroidism and growth, development, and childhood intelligence: a meta-analysis. J Clin Res Pediatr Endocrinol. 2018;10(2):153–161.
  • Zhang Y, Wang H, Pan X, et al. Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: a systematic review and meta-analysis. PLoS One. 2017;12(4):e0175708.
  • Maraka S, Ospina NM, O’Keeffe DT, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid. 2016;26(4):580–590.
  • Velkeniers B, Van Meerhaeghe A, Poppe K, et al. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update. 2013;19(3):251–258.
  • Tang R, Wang J, Yang L, et al. Subclinical hypothyroidism and depression: a systematic review and meta-analysis. Front Endocrinol. 2019;10:340.
  • Loh HH, Lim LL, Yee A, et al. Association between subclinical hypothyroidism and depression: an updated systematic review and meta-analysis. BMC Psychiatry. 2019;19(1):12.
  • Bode H, Ivens B, Bschor T, et al. Association of hypothyroidism and clinical depression: a systematic review and meta-analysis. JAMA Psychiatry. 2021;78(12):1375–1383.
  • Khaleghzadeh-Ahangar H, Talebi A, Mohseni-Moghaddam P. Thyroid disorders and development of cognitive impairment: a review study. Neuroendocrinology. 2022;112(9):835–844.
  • Rieben C, Segna D, da Costa BR, et al. Subclinical thyroid dysfunction and the risk of cognitive decline: a meta-analysis of prospective cohort studies. J Clin Endocrinol Metab. 2016;101(12):4945–4954.
  • Akintola AA, Jansen SW, van Bodegom D, et al. Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis. Front Aging Neurosci. 2015;7:150.
  • Pasqualetti G, Pagano G, Rengo G, et al. Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(11):4240–4248.
  • Yin JJ, Liao LM, Luo DX, et al. Spatial working memory impairment in subclinical hypothyroidism: an FMRI study. Neuroendocrinology. 2013;97(3):260–270.
  • Najafi L, Malek M, Hadian A, et al. Depressive symptoms in patients with subclinical hypothyroidism–the effect of treatment with levothyroxine: a double-blind randomized clinical trial. Endocr Res. 2015;40(3):121–126.
  • Wildisen L, Feller M, Del Giovane C, et al. Effect of levothyroxine therapy on the development of depressive symptoms in older adults with subclinical hypothyroidism: an ancillary study of a randomized clinical trial. JAMA Netw Open. 2021;4(2):e2036645.
  • Costantine MM, Smith K, Thom EA, et al. Effect of thyroxine therapy on depressive symptoms among women with subclinical hypothyroidism. Obstet Gynecol. 2020;135(4):812–820.
  • Büchi AE, Feller M, Netzer S, et al. Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: a nested study within a randomized placebo controlled trial. Bone. 2022;161:116404.
  • Gonzalez Rodriguez E, Stuber M, Del Giovane C, et al. Skeletal effects of levothyroxine for subclinical hypothyroidism in older adults: a TRUST randomized trial nested study. J Clin Endocrinol Metab. 2020;105:dgz058.
  • Segna D, Bauer DC, Feller M, et al. Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts. J Intern Med. 2018;283(1):56–72.
  • Yan Z, Huang H, Li J, et al. Relationship between subclinical thyroid dysfunction and the risk of fracture: a meta-analysis of prospective cohort studies. Osteoporos Int. 2016;27(1):115–125.
  • Blum MR, Bauer DC, Collet TH, et al. Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015;313(20):2055–2065.
  • Zhu H, Zhang J, Wang J, et al. Association of subclinical thyroid dysfunction with bone mineral density and fracture: a meta-analysis of prospective cohort studies. Endocrine. 2020;67(3):685–698.
  • Wirth CD, Blum MR, da Costa BR, et al. Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis. Ann Intern Med. 2014;161(3):189–199.
  • Tsuda S, Nakayama M, Matsukuma Y, et al. Subclinical hypothyroidism is independently associated with poor renal outcomes in patients with chronic kidney disease. Endocrine. 2021;73(1):141–150.
  • Zhou JB, Li HB, Zhu XR, et al. Subclinical hypothyroidism and the risk of chronic kidney disease in T2D subjects: a case-control and dose-response analysis. Medicine. 2017;96(15):e6519.
  • Zahler D, Izkhakov E, Rozenfeld KL, et al. Relation of subclinical hypothyroidism to acute kidney injury among st-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention. Isr Med Assoc J. 2019;21(10):692–695.
  • Chen Y, Wu G, Xu M. The effect of L-thyroxine substitution on oxidative stress in early-stage diabetic nephropathy patients with subclinical hypothyroidism: a randomized double-blind and placebo-controlled study. Int Urol Nephrol. 2018;50(1):97–103.
  • Hennessey JV, Weir MR, Soni-Brahmbhatt S, et al. Effect of levothyroxine on kidney function in chronic kidney disease with subclinical hypothyroidism in US veterans: a retrospective observational cohort study. Adv Ther. 2021;38(2):1185–1201.
  • Biondi B. Levothyroxine and the heart. In: Kahaly GJ, editor. 70 Years of levothyroxine. Cham (CH): Springer; March 12, 2021. 85–96.
  • Udovcic M, Pena RH, Patham B, et al. Hypothyroidism and the heart. Methodist Debakey Cardiovasc J. 2017;13(2):55–59.
  • Corona G, Croce L, Sparano C, et al. Thyroid and heart, a clinically relevant relationship. J Endocrinol Invest. 2021;44(12):2535–2544.
  • Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American heart association. Circulation. 2021;143(21):e984–e1010.
  • Rotondi M, Magri F, Chiovato L. Thyroid and obesity: not a one-way interaction. J Clin Endocrinol Metab. 2011;96(2):344–346.
  • Rotondi M, Leporati P, La Manna A, et al. Raised serum TSH levels in patients with morbid obesity: is it enough to diagnose subclinical hypothyroidism? Eur J Endocrinol. 2009;160(3):403–408.
  • Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534–2544.
  • Stuber MJ, Moutzouri E, Feller M, et al. Effect of thyroid hormone therapy on fatigability in older adults with subclinical hypothyroidism: a nested study within a randomized placebo-controlled trial. J Gerontol A Biol Sci Med Sci. 2020;75(9):e89–e94.
  • Razvi S, Ingoe L, Ryan V, et al. Study of optimal replacement of thyroxine in the elderly (SORTED) – results from the feasibility randomised controlled trial. Thyroid Res. 2016;9:5.
  • Razvi S, Ryan V, Ingoe L, et al. Age-related serum thyroid-stimulating hormone reference range in older patients treated with levothyroxine: a randomized controlled feasibility trial (SORTED 1). Eur Thyroid J. 2020;9(1):40–48.
  • Mooijaart SP, Du Puy RS, Stott DJ, et al. Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidism. JAMA. 2019;322(20):1977–1986.
  • Razvi S, Arnott B, Teare D, et al. Multinational survey of treatment practices of clinicians managing subclinical hypothyroidism in older people in 2019. Eur Thyroid J. 2021;10(4):330–338.
  • Toft DJ. A third of >1000 patients treated for hypothyroidism may not require thyroid hormone therapy. Clin Thyroidol. 2021;33(1):14–16.
  • Gallizzi R, Crisafulli C, Aversa T, et al. Subclinical hypothyroidism in children: is it always subclinical? Ital J Pediatr. 2018;44(1):25.
  • Crisafulli G, Aversa T, Zirilli G, et al. Subclinical hypothyroidism in children: When a replacement hormonal treatment might be advisable. Front Endocrinol. 2019;10:109.
  • Kapelari K, Kirchlechner C, Högler W, et al. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord. 2008;8:15.
  • Society for Endocrinology, British Thyroid Association. Society for Endocrinology & British Thyroid Association issue statement against new treatment recommendations for subclinical hypothyroidism; [cited 2022 Aug]. Available from: https://www.endocrinology.org/press/press-releases/society-for-endocrinology-british-thyroid-association-issue-statement-against-new-treatment-recommendations-for-subclinical-hypothyroidism/#.
  • Gottwald-Hostalek U, Razvi S. Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations. Curr Med Res Opin. 2022;2022:1–6.
  • Gottwald-Hostalek U, Kahaly GJ. Triiodothyronine alongside levothyroxine in the management of hypothyroidism? Curr Med Res Opin. 2021;37(12):2099–2106.